Review
OPA1-associated disorders: Phenotypes and pathophysiology

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Abstract

The OPA1 gene, encoding a dynamin-like mitochondrial GTPase, is involved in autosomal dominant optic atrophy (ADOA, OMIM #165500). ADOA, also known as Kjer's optic atrophy, affects retinal ganglion cells and the axons forming the optic nerve, leading to progressive visual loss. OPA1 gene sequencing in patients with hereditary optic neuropathies indicates that the clinical spectrum of ADOA is larger than previously thought. Specific OPA1 mutations are responsible for several distinct clinical presentations, such as ADOA with deafness (ADOAD), and severe multi-systemic syndromes, the so-called “ADOA plus” disorders, which involve neurological and neuromuscular symptoms similar to those due to mitochondrial oxidative phosphorylation defects or mitochondrial DNA instability. The study of the various clinical presentations of ADOA in conjunction with the investigation of OPA1 mutations in fibroblasts from patients with optic atrophy provides new insights into the pathophysiological mechanisms of the disease while underscoring the multiple physiological roles played by OPA1 in energetic metabolism, mitochondrial structure and maintenance, and cell death. Finally, OPA1 represents an important new paradigm for emerging neurodegenerative diseases affecting mitochondrial structure, plasticity and functions.

Introduction

The optic nerve transmits visual information from the neurosensory retina to the visual cortex. In humans, each optic nerve, comprising about 1.2 million axons emerging from the retinal ganglion cells (RGCs), receives visual information from retinal photoreceptors. At the surface of the retina, the axons of the RGCs form the retinal nerve fibre layer (RNFL), and converge to the head of the optic nerve, or optic disc (Fig. 1a). After exiting the eye, these axons become myelinated and carry visual information to the lateral geniculate nucleus in the thalamus. Loss of RGCs or their axons leads to optic neuropathy, manifested on ophthalmoscopic examination as optic disc pallor or, at a more severe stage, as optic atrophy (Fig. 1b). However, optic atrophy is not a specific finding in hereditary optic neuropathies, and many other conditions, including compression, infiltration, inflammation, ischemia, toxicity or nutritional deficiencies may give rise to similar ophthalmoscopic aspects.

Hereditary optic atrophies were first described at the end of the 19th century by two British ophthalmologists, Frederick Batten and Simeon Snell (Batten, 1896, Snell, 1897). A quarter century earlier, the German ophthalmologist, Leber (1871) had reported an ophthalmologic disorder, today known as Leber's hereditary optic neuropathy (LHON). Less than a century later, the Danish ophthalmologist Poul Kjer reported 19 families suffering from a dominantly inherited optic atrophy, now called autosomal dominant optic atrophy (ADOA, MIM #165500) (Kjer, 1959) or Kjer's optic atrophy. The locus for the main ADOA-causing gene, optic atrophy 1 (OPA1, MIM *605290), was mapped to chromosome 3q28-29 (Eiberg et al., 1994, Lunkes et al., 1995). Subsequently, ADOA was found to be genetically heterogeneous as two further loci were identified, namely OPA4 (MIM %605293) and OPA5 (MIM %610708), mapping to chromosomes 18q12.2-q12.3 (Kerrison et al., 1998) and 22q12.1-q13.1 (Barbet et al., 2005), respectively. Other hereditary optic neuropathies include X-linked optic atrophy (XLOA), OPA2 (MIM %311050), mapping to locus Xp11.4-p11.21 (Assink et al., 1997), and autosomal recessive optic atrophies (AROA), OPA3 (MIM #165300) and OPA6 (MIM %258500), mapping to chromosomes 19q13.2-13.3 and 8q21-q22, respectively (Barbet et al., 2003). Moreover, some hereditary optic neuropathies, such as OPA7, with extra-ophthalmologic features extending to the auditory system, can be part of broader syndromic presentations (Carelli et al., 2007).

LHON, with a prevalence ranging from 1/30,000 to 1/50,000 (Man et al., 2003, Puomila et al., 2007), and ADOA, with a prevalence of 1/50,000 (Lyle, 1990), are the most common forms of hereditary optic neuropathies. Interestingly, due to a founder effect, ADOA is more prevalent in Denmark (1/10,000) than in any other part of the world (Kjer et al., 1996, Thiselton et al., 2001). Indeed, in the Danish population, the c.2826delT mutation is highly prevalent and is supposed to have been introduced at least 69 generations ago, before the Viking era (Thiselton et al., 2001).

LHON, which has a maternal mode of inheritance, was the first disease for which a mutation in the mitochondrial DNA (mtDNA), namely m.11778G>A, was identified (Wallace et al., 1988). Thereafter, a dozen of other LHON-causing mtDNA mutations, mainly affecting the genes encoding subunits of respiratory chain complex I, the NADH-ubiquinol oxidoreductase, have been identified (Ruiz-Pesini et al., 2007; http://www.mitomap.org/), three of them representing about 95% of the total (m.11778G>A, m.3460G>A, m.14484T>C). The involvement of respiratory chain dysfunctions in LHON underscores the strong dependency of RGCs on energetic requirements.

In 2000, the links between hereditary optic atrophy and mitochondria were strengthened by the identification of OPA1, a gene encoding a dynamin-like mitochondrial GTPase, as the main gene involved in ADOA (Delettre et al., 2000, Alexander et al., 2000). The finding that OPA1 proteins are involved in mitochondrial network structure and morphology opened new avenues for the understanding of neurodegenerative pathomechanisms. In 2004, further arguments supporting mitochondrial involvement in the pathophysiology of hereditary optic neuropathies were provided by the discovery of dominant mutations in OPA3, another gene encoding an inner mitochondrial protein, in a syndrome associating ADOA and cataract (ADOAC, MIM #165300) (Reynier et al., 2004).

Since 2000, the systematic sequencing of the OPA1 gene in patients presenting various clinical aspects of optic neuropathies has revealed a large spectrum of clinical phenotypes due to OPA1 mutations. Today, in our experience, up to 10% of patients carrying OPA1 mutations are affected with extra-ophthalmological abnormalities in association with optic neuropathy, showing that OPA1 may be responsible for a continuum of phenotypes ranging from mild disorders affecting only the RGCs to severe and multi-systemic diseases.

In the present report, we review the spectrum of clinical presentations due to OPA1 mutations, and discuss the molecular and cellular mechanisms involved in the pathophysiology of OPA1-associated disorders.

Section snippets

Clinical description of ADOA

ADOA is classically described as an isolated optic neuropathy, with an insidious onset during the first two decades of life. Simultaneous involvement of the two optic nerves typically results in a bilateral, usually progressive visual loss, related to centroceccal, central or paracentral scotomas, although bitemporal paracentral defects are a common feature of the disease (Fig. 2). The precise age of onset is almost never clearly established, most of the patients being diagnosed when entering

OPA1 is the major gene associated with ADOA

Although OPA1 mutations are the main genetic cause of ADOA, the genetic aetiology of the disease remains heterogeneous. The detection rate of OPA1 mutations in ADOA families is highly variable, ranging from 32% to 89% according to reports, but this is probably due to the different clinical criteria used for the selection of patients (Pesch et al., 2001, Delettre et al., 2001, Toomes et al., 2001, Thiselton et al., 2002, Marchbank et al., 2002, Baris et al., 2003, Cohn et al., 2007).

OPA1-related

Variable expressivity of ADOA

The systematic molecular screening of OPA1 in patients with ADOA has revealed a wide range of phenotypic variations of the disease. The detection of OPA1 mutations showed that many of the cases of optic atrophy, which would not have been classified as ADOA on the basis of clinical criteria, were in fact related to the disease. The various clinical presentations of ADOA are described below and the main characteristics are summed up in Table 1.

OPA1 mutational spectrum

The OPA1 gene located on chromosome 3q28-29 spans approximately 100 kb and is composed of 30 coding exons including three alternative exons (4, 4b and 5b), resulting in eight OPA1 transcript variants (Delettre et al., 2001). The main isoform (isoform 1) encoded by a 2880 nucleotide-long open reading frame, excluding exon 4b and 5b, is a 960 amino acid protein, whereas the longest open reading frame, including all alternative exons, encodes a predicted 1015 amino acid protein. OPA1 is

Haploinsufficiency or dominant negative effect?

The genetics of OPA1-related ADOA are more complex and diverse than initially expected. The preponderance of OPA1 mutations leading to premature translation terminations and null mutations, strongly suggests that haploinsufficiency is the main pathogenic mechanism. The description of a large 560–860 kb deletion revealed by FISH, resulting in the complete loss of one copy of the OPA1 gene, provided additional evidence that haploinsufficiency is probably responsible for ADOA (Marchbank et al., 2002

Genetic counselling

ADOA is inherited in an autosomal dominant manner so that each child of an individual bearing an OPA1 mutation has a 50% risk of inheriting the mutant allele. However, genetic counselling remains complicated by the incomplete penetrance and the marked variable inter- and intra-familial expressivity of the disease. In addition, with the exception of syndromic ADOA, genotype-phenotype correlations are very rare. Consequently, the likelihood of an OPA1 mutation carrier to become affected by severe

Future prospects and therapeutic perspectives

Studies of patients carrying pathogenic OPA1 mutations have revealed the great diversity of clinical presentations of ADOA, the energetic impairment associated with the disease, and the newly established relationship between OPA1 dysfunction and mtDNA instability. Much remains to be done to elucidate the complex links between energetic metabolism, ROS production, mtDNA metabolism, mitochondrial structure and plasticity, cell death, axonal transport and neurodegeneration. Since OPA1 appears to

Acknowledgements

We are grateful to Kanaya Malkani for critical reading and comments on the manuscript. Our work is supported by INSERM, the University Hospital of Angers (PHRC 04-12), the University of Angers, France; Forskningsrådet for Sundhed og Sygdom, Denmark; and by grants from the following patients’ associations: “Association contre les Maladies Mitochondriales (AMMi)”, “Ouvrir les Yeux (OLY)”, “Retina France” and “Union Nationale des Aveugles et Déficients Visuels (UNADEV)”.

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